First steps New insights into the cause of motor neurone disease have been uncovered with a study showing mutations in a specific gene lead to the death of the nerve cells responsible for powering our muscles.

The collaborative study led by Stanford University has been searching for the genetic causes of the disease, also known as Lou Gehrig's disease after the famous US baseball player or amyotrophic lateral sclerosis (ALS).

Australian co-author Associate Professor Ian Blair, from the Australian School of Advanced Medicine at Macquarie University, says there are two forms of the disease.

About 10 per cent of cases have a family history of the disease, while the majority of cases are sporadic ALS.

"In the past few years there have been a lot of breakthroughs in the familial form, but sporadic ALS has been a really hard nut to crack," says Blair.

He says it has long been suspected that gene mutations were behind sporadic ALS, but the technology has not been available to test this theory.

However recent dramatic advances in genome sequencing technology - known as next-generation sequencing - have now made testing this possible.

Progressive paralysis

"It specifically targets the motor neurons that pass the signal to move limbs and also are critical to talking, swallowing, eating and breathing," says Blair.

"In most cases the mind is spared so these people are completely aware of what is happening to them but progressively become unable to move and unable to communicate."

Blair says in Australia about one in 5000 people aged over 50 will be affected with more deaths annually from ALS than HIV/AIDS.

In the study published today in Nature Neuroscience , the researchers analysed the genomes of about 50 sporadic ALS trios - the affected patient and both biological parents, who have no history of the disease.

The team was searching for de novo mutations, which are defects in the gene that are not present in either parent and have occurred for the first time in the patient.

They found a mutation in the CREST gene, which is expressed more abundantly in neurons, in one of these patients.

Blair says the Australian element of the study was to screen for mutations in the CREST gene in a large collection of familial ALS samples.

"If this protein is so critical that when it is mutated it can lead to the death of motor neurones, it is reasonable to assume mutations in this gene might also occur in familial ALS," says Blair.

"We found a mutation in a family, so that strongly supported the role for CREST in causing the disease."

First step

These findings were also supported by laboratory tests that showed these mutations caused dysfunction in neuronal cells.

"This is the first step," says Blair. "It highlights what is wrong, now the challenge is to uncover how that is causing the death of motor neurons."

Blair says the finding adds to the bank of knowledge about ALS and can help to develop effective models of the disease on which to test new therapies.

"We are trying to find the smoking gun that causes this disease," he says. "Each gene [we discover] might be that smoking gun that allows us to develop models to help us to develop therapies."

Blair says the approach they have used to uncover these mutations could be applied to all neurodegenerative diseases such as Parkinson's and Alzheimer's disease.